PROJECT SUMMARY/ABSTRACT The neurovascular interface fundamentally changes during CNS diseases due to increased blood-brain barrier permeability and influx of plasma proteins in the CNS parenchyma. Studying neurologic diseases through the multidisciplinary prism of vascular biology, immunology, and neuroscience could be critical for the identification of novel mechanisms of disease, discovery of imaging tools and therapeutic treatments for a wide range of neurologic diseases characterized by BBB disruption. In my laboratory we made unanticipated discoveries on the functional role of BBB disruption in CNS autoimmunity, glial cell activation, and neurodegeneration. We identified leakage of blood proteins in the brain and neurotrophin receptor signaling as novel molecular mediators at the neurovascular interface that regulate glial ? neuron cross-talk and the communication between the brain and the immune system. Furthermore, we developed novel methods for high-resolution two-photon microscopy of the neurovascular interface in vivo. Our aim is to understand the mechanisms that control the communication between the brain, immune and vascular systems with the ultimate goal to design novel therapies for neurologic diseases. In this application we propose a multipronged approach to determine the role of neurovascular dysfunction in neurodegeneration, CNS repair, and glial cell biology and discover novel genetic regulatory circuits that control vascular-driven CNS innate immune mediated neurotoxicity. We use an innovative experimental design consisting of in vivo two-photon, super-resolution and electron microscopy of the neurovascular interface, electrophysiology, cell biology and signal transduction, new genetic tools and animal models, and genomic and proteomic approaches. The proposed studies will set the foundation how neurovascular dysfunction regulates brain functions and the outcomes of this research would be applicable for the understanding of the etiology and the development of new treatments for several neurologic diseases, such as multiple sclerosis, stroke, spinal cord and brain injury.